Protective VEGF Inhibition for Isotoxic Dose Escalation in Glioblastoma (PRIDE)

A Phase IIa, Open-label, Multicenter Study of Radiochemotherapy With Isotoxic Dose Escalation and Protective VEGF Inhibition Using Bevacizumab in the Treatment of Patients With First Diagnosis of IDH Wild-type, MGMT Unmethylated Glioblastoma

Glioblastoma is the most aggressive brain tumor and often recurs locally despite intensive treatment. Standard chemoradiotherapy with 60 Gy may not be sufficient to control the tumor, and dose escalation seems to be warranted, but causes more toxicity. To address this, the multicentric PRIDE trial employs two cycles of bevacizumab to achieve dose escalation isotoxically. The goal is improved survival without significantly increasing side effects. The study uses a simultaneous integrated boost with a total dose of 75 Gy in 2.5 Gy per fraction.

Study Overview

• Status: Recruiting
• Conditions: Glioblastoma
• Intervention / Treatment: Radiation: Dose escalation of radiation dose beyond the therapeutic standard

• Study Type: Interventional
• Enrollment (Estimated): 146
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ulrike Plugradt; Phone Number: 004989440074770; Email: Ulrike.Pflugradt@med.uni-muenchen.de

Study Locations

• Germany
  • Munich, Germany, 81377
    • Recruiting
    • Department of Radiation Oncology
    • Contact: Maximilian Niyazi, Prof.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• IDH wild-type, MGMT unmethylated glioblastoma patients
• Informed consent
• Age ≥18 and ≤ 70 years, smoking or non-smoking, of any ethnic origin
• ECOG 0-2
• Neutrophil counts > 1500/μl; Platelet counts > 100.000/μl; Hemoglobin > 8 g/dl; Serum creatinine < 1.5-fold upper limit of normal (ULN); Bilirubin, AST or ALT < 2.5-fold ULN unless attributed to anticonvulsants; Alkaline phosphatase < 2.5-fold ULN
• Adequate contraception
• Serum creatinine ≤ 1.5 x ULN AND patients with urine dipstick for proteinuria < 2+. Patients with ≥ 2+ proteinuria on dipstick urinalysis at baseline should show urine protein to creatinine ratio ≤ 1

Exclusion Criteria:

• Evidence of recent hemorrhage on postoperative MRI of the brain
• Subjects on any drug suspected to interfere with bevacizumab at the time of study inclusion
• Immuno-compromised patients, including known seropositivity for human immunodeficiency virus (HIV)
• Known hypersensitivity to any component of the investigational drugs or excipients (allergy to or other intolerability of bevacizumab or excipients)
• Any other significant medical illness or medically significant laboratory finding that would, in the investigator's judgement, make the patient inappropriate for this study, or would increase the risk associated with the patients' participation in the study
• Incapability to undergo MRI
• Prior treatment with bevacizumab for any indication
• Significant cardiovascular disease defined as congestive heart failure (NYHA Class II, III, IV), unstable angina pectoris, or myocardial infarction within 6 months prior to enrolment
• Inadequately controlled hypertension (de-fined as a blood pressure of > 150 mmHg systolic and/or >100 mmHg diastolic on medication), or any prior history of hypertensive crisis or hypertensive encephalopathy
• History of stroke or transient ischemic attack within 6 months prior to enrolment
• Significant vascular disease (e.g. aortic aneurysm, aortic dissection or recent peripheral arterial thrombosis) within 6 months prior to enrolment
• Evidence or history of recurrent thromboembolism (> 1 episode of deep venous thrombosis / peripheral embolism) during the past 2 years
• Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)
• Chronic daily intake of aspirin > 325 mg/day or clopidogrel > 75 mg /day
• History of intracranial abscess within 6 months prior to inclusion
• History of abdominal or tracheo-oesophageal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrolment
• History of ≥ grade 2 hemoptysis according to NCI-CTC criteria within 1 month prior to inclusion
• Serious non-healing wound, ulcer or bone fracture

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 75 Gy with two cycles of bevacizumab	Radiation: Dose escalation of radiation dose beyond the therapeutic standard; Dose escalation to 75 Gy with concomitant radioprotectant bevacizumab; Other Names: bevacizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OS	Overall Survival	Date of study inclusion (informed consent) to death or end of F/U

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability	Safety and tolerability of dose escalation with bevacizumab according to CTCAE v5.0	Date of study inclusion (informed consent) to death or end of F/U
PFS-6	6 months rate of progression-free survival	6 months after the date of study inclusion (informed consent)
PFS	Progression-free survival	Date of study inclusion (informed consent) to death or progression
QoL	Quality of life as determined by EORTC QLQ-C30/QLQ-BN 20	Date of study inclusion (informed consent) to death or end of F/U
Cognitive function	Cognitive function determined by standard test batteries	Date of study inclusion (informed consent) to death or end of F/U
Exploratory objective	Validation of prognostic 4-miRNA signature-based risk score	Date of study inclusion (informed consent) to death or end of F/U

Collaborators and Investigators

• Sponsor: Ludwig-Maximilians - University of Munich
• Investigators: Principal Investigator: Maximilian Niyazi, Prof. Dr., University Hospital, LMU Munich

Study record dates

Study Major Dates

• Study Start (Actual): April 10, 2024
• Primary Completion (Estimated): April 10, 2027
• Study Completion (Estimated): July 10, 2027

Study Registration Dates

• First Submitted: April 30, 2023
• First Submitted That Met QC Criteria: May 13, 2023
• First Posted (Actual): May 23, 2023

Study Record Updates

• Last Update Posted (Actual): April 16, 2024
• Last Update Submitted That Met QC Criteria: April 12, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: bevacizumab; Dose escalation; VMAT; VEGF inhibition; FET PET
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: 2021-000565-32

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No